scholarly journals Cefoperazone/sulbactam therapeutic drug monitoring in patients with liver cirrhosis: Potential factors affecting the pharmacokinetic/pharmacodynamic target attainment

2019 ◽  
Vol 125 (4) ◽  
pp. 353-359 ◽  
Author(s):  
Yuzhu Dong ◽  
Ying Li ◽  
Ying Zhang ◽  
Tao Zhang ◽  
Li Zhu ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Factors Affecting ◽  
Potential Factors

scholarly journals P99 Clinical validation of published vancomycin population PK models in critically ill neonates

2019 ◽  
Vol 104 (6) ◽  
pp. e58.2-e59
Author(s):  
A van der Veen ◽  
RJ Keizer ◽  
W de Boode ◽  
A Somers ◽  
R Brüggemann ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
A Priori ◽  
Predictive Performance ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Suitable Model ◽  
List Type ◽  
A Posteriori ◽  
Target Attainment

BackgroundVancomycin is commonly used for treatment of severe Gram+ neonatal infections. Currently, even with the use of optimized dosing regimens and therapeutic drug monitoring (TDM), target attainment rates are abominable, leaving patients at risk for therapeutic failure and toxicity. Model-informed precision dosing (MIPD) offers a large potential to improve therapy in the individual patient.The aim of this study was to identify a suitable model for bedside MIPD by assessing the predictive performance of published population pharmacokinetic (popPK) models.MethodsA literature search was conducted to identify parametric popPK models. PK vancomycin data were retrospectively collected from NICU patients at the Radboud University Hospital, Nijmegen, The Netherlands. The model predictive performance was assessed by comparison of predictions to observations, calculation of bias (Mean Percentage Errors, MPE) and imprecision (Normalized Root Mean Squared Errors, NRMSE). Evaluations included both a priori (model covariate input) and a posteriori (model covariate and TDM concentration input) scenarios.Results265 TDM measurements from 65 neonates (median postmenstrual age:32 weeks [range:25–45 weeks]; median weight:1281g [range:597–5360g]; median serum creatinine:0,48 mg/dL [range:0,15–1,28 mg/dL]) were used for model evaluation. Six popPK models were evaluated1–6. A posteriori predictions of all models were consistently more accurate and precise compared to the a priori (starting dose) predictions. PopPK models of Frymoyer et al. and Capparelli et al. consistently performed best through all evaluations in both the a priori and a posteriori scenario (MPE ranging from -18 to 6,4% in a priori scenario and -6,5 to -3,8% in a posteriori scenario; NRMSE ranging from 34 to 40% in a priori scenario and 23 to 24% in a posteriori scenario).ConclusionLarge differences in predictive performance of popPK models were observed. Repeated therapeutic drug monitoring remains necessary to increase target attainment rate. Best performing models for bedside MIPD were identified in our patient population.ReferencesZhao W, Lopez E, Biran V, et al. ( 2013). Vancomycin continuous infusion in neonates: Dosing optimisation and therapeutic drug monitoring. Arch Dis Child;98(6):449–453.Capparelli EV, Lane JR, Romanowski GL, et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. J Clin Pharmacol, 41:927–934.De Cock RFW, Allegaert K, Brussee JM, et al. ( 2014). Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. Pharm Res;31(10):2642–2654.Frymoyer A, Hersh AL, El-Komy MH, et al. ( 2014). Association between vancomycin trough concentration and area under the concentration-time curve in neonates. Antimicrob Agents Chemother, 58(11):6454–6461.Anderson BJ, Allegaert K, Van Den Anker JN, Cossey V, Holford NHG. ( 2006). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br J Clin Pharmacol;63(1):75–84.Germovsek E, Osborne L, Gunaratnam F, Lounis SA, Busquets FB, Sinha AK. ( 2019). Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data. J Antimicrob Chemother, 1–9.Disclosure(s)R. Keizer is an employee and stockholder of InsightRX.

scholarly journals Model-Optimized Fluconazole Dose Selection for Critically Ill Patients Improves Early Pharmacodynamic Target Attainment without the Need for Therapeutic Drug Monitoring

2020 ◽  
Vol 65 (3) ◽  
Author(s):  
Indy Sandaradura ◽  
Jessica Wojciechowski ◽  
Deborah J. E. Marriott ◽  
Richard O. Day ◽  
Sophie Stocker ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Fungal Infections ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Dose Selection ◽  
Dose Individualization

ABSTRACT Fluconazole has been associated with higher mortality compared with the echinocandins in patients treated for invasive candida infections. Underexposure from current fluconazole dosing regimens may contribute to these worse outcomes, so alternative dosing strategies require study. The objective of this study was to evaluate fluconazole drug exposure in critically ill patients comparing a novel model-optimized dose selection method with established approaches over a standard 14-day (336-h) treatment course. Target attainment was evaluated in a representative population of 1,000 critically ill adult patients for (i) guideline dosing (800-mg loading and 400-mg maintenance dosing adjusted to renal function), (ii) guideline dosing followed by therapeutic drug monitoring (TDM)-guided dose adjustment, and (iii) model-optimized dose selection based on patient factors (without TDM). Assuming a MIC of 2 mg/liter, free fluconazole 24-h area under the curve (fAUC24) targets of ≥200 mg · h/liter and <800 mg · h/liter were used for assessment of target attainment. Guideline dosing resulted in underexposure in 21% of patients at 48 h and in 23% of patients at 336 h. The TDM-guided strategy did not influence 0- to 48-h target attainment due to inherent procedural delays but resulted in 37% of patients being underexposed at 336 h. Model-optimized dosing resulted in ≥98% of patients meeting efficacy targets throughout the treatment course, while resulting in less overexposure compared with guideline dosing (7% versus 14%) at 336 h. Model-optimized dose selection enables fluconazole dose individualization in critical illness from the outset of therapy and should enable reevaluation of the comparative effectiveness of this drug in patients with severe fungal infections.

Accuracy of Empiric Gentamicin Dosing Guidelines in Neonates

2010 ◽  
Vol 15 (4) ◽  
pp. 264-273
Author(s):  
Anna E. Hitron ◽  
Yao Sun ◽  
Sarah B. Scarpace
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Gestational Age ◽  
Drug Monitoring ◽  
Dose Interval ◽  
Pharmacokinetic Modeling ◽  
Therapeutic Drug ◽  
Potential Factors ◽  
New Guidelines ◽  
Dosing Accuracy ◽  
Current Guidelines

ABSTRACT OBJECTIVE To evaluate the accuracy of a neonatal gentamicin nomogram to achieve therapeutic gentamicin serum concentrations without further adjustment, allowing for decreased serum drug monitoring METHODS Retrospective single center review of all gentamicin pharmacokinetic evaluations in patients ≤ 30 days of life from July 2005 – June 2007. Patients were evaluated for postnatal age, gestational age, weight, serum creatinine, dose/interval, serum drug peaks and troughs, results of discharge hearing test and recent use of indomethacin. Logistic regression was utilized to determine potential factors impacting overall dosing accuracy, potentially allowing for decreased therapeutic drug monitoring. Factors found to be significant were incorporated into new guidelines which were evaluated through pharmacokinetic modeling. RESULTS Overall accuracy rate was 84% when empiric dosing guidelines were utilized; 16% of all doses were changed due to supratherapeutic troughs and 1% were changed due to subtherapeutic peaks. Variables found to impact the necessity for dose changes incuded gestational age (p≤0.001), weight (p≤0.001), indomethacin use (p≤0.001), number of indomethacin doses used (p≤0.001 and p=0.009 for 1–3 and 4–6 doses, respectively), and SCr in patients ≥ 7 days old (p=0.028); however, only gestational age remained a significant predictor when all other factors were considered (p=0.008). The current guidelines were changed to account for increased troughs in patients ≤ 28 weeks gestation and examined through pharmacokinetic modeling. Pharmacokinetic modeling of the new guidelines predicted an overall accuracy of 94%. CONCLUSIONS From the data gathered regarding the accuracy in patients ≥ 35 weeks gestation, we recommend to decrease therapeutic drug monitoring within this cohort. Utilizing the results of regression analysis, the current guidelines have been adjusted to allow for increased clearance in patients ≤ 28 weeks gestation, although they still need to be prospectively evaluated.

scholarly journals Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness—Experience and Recommendations from One Year in Routine Clinical Practice

Antibiotics ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 131
Author(s):  
Christina Scharf ◽  
Michael Paal ◽  
Ines Schroeder ◽  
Michael Vogeser ◽  
Rika Draenert ◽  
...  
Keyword(s):  
Renal Function ◽  
Clinical Practice ◽  
Therapeutic Drug Monitoring ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Therapeutic Drug ◽  
Beta Lactam ◽  
Target Attainment ◽  
Number Of Patients

Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem, r = 0.53; piperacillin, r = 0.63). Patients with renal replacement therapy or creatinine clearance (CrCl) of <70 mL/min had high rates of target attainment with the standard dosing regimens. There was a low number of patients with a CrCl >100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment.

Antifungal therapeutic drug monitoring

2017 ◽  
Author(s):  
H. Ruth Ashbee
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Antifungal Therapy ◽  
Drug Monitoring ◽  
Antifungal Drug ◽  
Therapeutic Drug ◽  
Time Intervals ◽  
Factors Affecting ◽  
Drug Concentrations ◽  
Specific Factors

Therapeutic drug monitoring (TDM), the process of measuring drug concentrations in patients at specified time intervals, aims to ensure that the drug concentrations remain within the efficacious and non-toxic range for that drug. This chapter reviews the rationale for the use of TDM in antifungal therapy, specifically for flucytosine and azoles, including fluconazole, itraconazole, voriconazole, and posaconazole. For each antifungal drug, the bioavailability and excretion of the drug are detailed, as well as specific factors affecting antifungal drug concentrations in patients. The chapter discusses the toxicities observed when antifungal drug concentrations exceed those which are safe in patients, and details the specific indications for the use of TDM.

scholarly journals Are Standard Dosing Regimens of Ceftriaxone Adapted for Critically Ill Patients with Augmented Creatinine Clearance?

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Julien Ollivier ◽  
Cédric Carrié ◽  
Nicolas d’Houdain ◽  
Sarah Djabarouti ◽  
Laurent Petit ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Creatinine Clearance ◽  
Critically Ill ◽  
Drug Monitoring ◽  
Critically Ill Patients ◽  
Free Fraction ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Dosing Regimens

ABSTRACT The objective of the present study was to determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic (PK)/pharmacodynamic (PD) target attainment in critically ill patients. Over a 9-month period, all critically ill patients treated with ceftriaxone were eligible. During the first 3 days of antimicrobial therapy, every patient underwent 24-h creatinine clearance (CLCR) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a CLCR of ≥150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/liter (percentage of the time that the concentration of the free fraction of drug remained greater than the MIC [fT>MIC], 100%). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimens for various MICs and three groups of CLCR (<150, 150 to 200, and >200 ml/min). Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). A CLCR of ≥150 ml/min was associated with empirical target underdosing with an odds ratio (OR) of 8.8 (95% confidence interval [CI] = 2.5 to 30.7; P < 0.01). Ceftriaxone PK concentrations were best described by a two-compartment model. CLCR was associated with unbound ceftriaxone clearance (P = 0.02). In the MCS, the proportion of patients who would have failed to achieve a 100% fT>MIC was significantly higher in ARC patients for each dosage regimen (OR = 2.96; 95% CI = 2.74 to 3.19; P < 0.01). A dose of 2 g twice a day was best suited to achieve a 100% fT>MIC. When targeting a 100% fT>MIC for the less susceptible pathogens, patients with a CLCR of ≥150 ml/min remained at risk of empirical ceftriaxone underdosing. These data emphasize the need for therapeutic drug monitoring in ARC patients.

scholarly journals Impact of dose adaptations following voriconazole therapeutic drug monitoring in pediatric patients

2019 ◽  
Vol 57 (8) ◽  
pp. 937-943 ◽  
Author(s):  
Vincent J Lempers ◽  
Edmé Meuwese ◽  
Annelies M Mavinkurve-Groothuis ◽  
Stefanie Henriet ◽  
Inge M van der Sluis ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Multiple Dose ◽  
Pediatric Patients ◽  
Therapeutic Drug ◽  
Target Attainment ◽  
Patient Demographics ◽  
Before And After ◽  
Intrapatient Variability ◽  
Trough Concentrations

Abstract Voriconazole is the mainstay of treatment for invasive aspergillosis in immunocompromised pediatric patients. Although Therapeutic Drug Monitoring (TDM) of voriconazole is recommended, it remains unknown if TDM-based dose adaptations result in target attainment. Patients <19 years from two pediatric hematologic-oncology wards were retrospectively identified based on unexplained high voriconazole trough concentrations (Cmin > 6 mg/l). Patient demographics, clinical characteristics, treatment, voriconazole dosing information, voriconazole Cmin before and after adjustment based on TDM were obtained. Twenty-one patients, median (range) age 7.0 (1.2–18.5) years, were identified in two centers. First Cmin (3.1 mg/l [0.1–13.5]) was obtained after 3 days (1–27) of treatment. The median of all Cmin (n = 485, median 11 per patient) was 2.16 mg/l (0.0 (undetectable)–28.0), with 24.1% of Cmin < 1 mg/l, 48.9% 1–4 mg/l, 9.3% 4–6 mg/l, and 17.7% > 6 mg/l. Intrapatient variability was large (94.1% for IV, 88.5% for PO). Dose increases at Cmin < 1 mg/l resulted in an increased Cmin in 76.4%, with 60% between 1 and 4 mg/l. Dose decreases at Cmin > 6 mg/l resulted in a decreased Cmin in 80%, with 51% between 1 and 4 mg/l. Overall, in 45% of the cases (33 out of 55 and 12 out of 45) therapeutic targets were attained after dose adjustment. Fifty-five percent of initial Cmin was outside the therapeutic target of 1–4 mg/l, with multiple dose adaptations required to achieve therapeutic concentrations. Only 60% and 51% of dose adaptations following sub- and supra-therapeutic Cmin, respectively, did result in target attainment. Intensive and continuous TDM of voriconazole is a prerequisite for ensuring adequate exposure in pediatric patients.

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